Role of pulsatile growth hormone (GH) secretion in the regulation of lipolysis in fasting humans.

BACKGROUND: The increase in growth hormone (GH) secretion during a prolonged fast stimulates lipolytic rate, thereby augmenting the mobilization of endogenous energy at a time when fuel availability is very low. STUDY AIM: To identify the specific component of GH secretory pattern responsible for the stimulation of lipolytic rate during fasting in humans. STUDY PROTOCOL: We measured lipolytic rate (using stable isotope dilution technique) after an overnight fast in 15 young, healthy, non-obese subjects (11 men and 4 women), and again on four separate occasions after a 59 h fast. These four prolonged fasting trials differed only by the contents of an infusion solution provided throughout the 59 h fasting period. Subjects were infused either with normal saline ("Control"; n = 15) or with graded doses of a GH Releasing Hormone Receptor Antagonist (GHRHa):10 µg/kg/h ("High"; n = 15), 1 µg /kg/h ("Medium"; n = 8), or 0.5 µg /kg/h ("Low"; n = 6). RESULTS: As expected, the 59 h fast completely suppressed plasma insulin levels and markedly increased endogenous GH concentrations (12 h vs 59 h Fast; p = 0.0044). Administration of GHRHa induced dose-dependent reduction in GH concentrations in response to the 59 h fast (p < 0.05). We found a strong correlation between the rate of lipolysis and GH mean peak amplitude (R = 0.471; p = 0.0019), and total GH pulse area under the curve (AUC) (R = 0.49; p = 0.0015), but not the GH peak frequency (R = 0.044; p = 0.8) or interpulse GH concentrations (R = 0.25; p = 0.115). CONCLUSION: During prolonged fasting (i.e., 2-3 days), when insulin secretion is abolished, the pulsatile component of GH secretion becomes a key metabolic regulator of the increase in lipolytic rate.

Suppression of growth hormone (GH) secretion by a selective GH-releasing hormone (GHRH) antagonist. Direct evidence for involvement of endogenous GHRH in the generation of GH pulses.

To study the potential involvement of growth hormone-releasing hormone (GHRH) in the generation of growth hormone (GH) pulses in humans we have used a competitive antagonist to the GHRH receptor, (N-Ac-Tyr1,D-Arg2)GHRH(1-29)NH2(GHRH-Ant). Six healthy young men were given a bolus injection of GHRH-Ant 400 micrograms/kg body wt or vehicle at 2200 h and nocturnal GH concentrations were assessed by every 10-min blood sampling until 0800 h. Integrated total and pulsatile GH secretion were suppressed during GHRH-Ant treatment by 40 +/- 6 (SE) % and 75 +/- 5%, respectively. GHRH-Ant suppressed maximum (7.6 +/- 2.2 vs 1.8 +/- 0.5 micrograms/liter; P < 0.001) and mean (3.3 +/- 1.0 vs 1.1 +/- 0.2 micrograms/liter; P = 0.02) GH pulse amplitudes. There was no change in integrated nonpulsatile GH levels, pulse frequency, or interpulse GH concentration. GHRH-Ant 400 micrograms/kg also suppressed the GH responses to intravenous boluses of GHRH 0.33 micrograms/kg given 1, 6, 12, and 24 h later by 95, 81, 59, and 4%, respectively. In five healthy men, the responses to 10-fold larger GHRH boluses (3.3 micrograms/kg) were suppressed by 82 and 0%, 1 and 6 h after GHRH-Ant 400 micrograms/kg, respectively. These studies provide the first direct evidence that endogenous GHRH participates in the generation of spontaneous GH pulses in humans.

Endogenous growth hormone (GH)-releasing hormone is required for GH responses to pharmacological stimuli.

The roles of hypothalamic growth hormone-releasing hormone (GHRH) and of somatostatin (SRIF) in pharmacologically stimulated growth hormone (GH) secretion in humans are unclear. GH responses could result either from GHRH release or from acute decline in SRIF secretion. To assess directly the role of endogenous GHRH in human GH secretion, we have used a competitive GHRH antagonist, (N-Ac-Tyr1,D-Arg2)GHRH(1-29)NH2 (GHRH-Ant), which we have previously shown is able to block the GH response to GHRH. We first tested whether an acute decline in SRIF, independent of GHRH action, would release GH. Pretreatment with GHRH-Ant abolished the GH response to exogenous GHRH (0.33 microgram/kg i.v.) but did not modify the GH rise after termination of an SRIF infusion. We then investigated the role of endogenous GHRH in the GH responses to pharmacologic stimuli of GH release. The GH responses to arginine (30 g i.v. over 30 min), L-dopa (0.5 g orally), insulin hypoglycemia (0.1 U/Kg i.v.), clonidine (0.25 mg orally), or pyridostigmine (60 mg orally) were measured in healthy young men after pretreatment with either saline of GHRH-Ant 400 microgram/kg i.v. In every case, GH release was significantly suppressed by GHRH-Ant. We conclude that endogenous GHRH is required for the GH response to each of these pharmacologic stimuli. Acute release of hypothalamic GHRH may be a common mechanism by which these compounds mediate GH secretion.

Negative feedback regulation of pulsatile growth hormone secretion by insulin-like growth factor I. Involvement of hypothalamic somatostatin.

To investigate the mechanisms of the negative feedback inhibition of growth hormone (GH) secretion by IGF-I, we studied parameters of GH pulsatility in six normal, fed men before and during a 48-h infusion of recombinant human IGF-I (rhIGF-I) (10-15 micrograms/kg per h). Plasma levels of IGF-I increased from the baseline value of 163.5 +/- 9.3 micrograms/liter (mean +/- SE) to a new steady state of 452.0 +/- 20.9 micrograms/liter during the infusion. Plasma GH concentrations were measured every 10 min for 24 h during both saline and rhIGF-I infusions using a sensitive chemiluminescent assay. Overall, GH concentrations were suppressed during the rhIGF-I infusion by 85 +/- 3%, mainly by attenuating spontaneous GH pulse amplitude (77 +/- 4% suppression). The apparent GH pulse frequency was attenuated from 7.8 +/- 0.9 to 4.7 +/- 0.6 pulses/24 h (P = 0.006). Administration of rhIGF suppressed GH responses to exogenous GH-releasing hormone by 82 +/- 3%, and thyroid-stimulating hormone responses to thyrotropin-releasing hormone were also suppressed by 44 +/- 9%. This constellation of hormonal effects is most compatible with the rhIGF-I-induced stimulation of hypothalamic somatostatin secretion.

Regulatory mechanisms of growth hormone secretion are sexually dimorphic.

Sexually dimorphic growth hormone (GH) secretory pattern is important in the determination of gender-specific patterns of growth and metabolism in rats. Whether GH secretion in humans is also sexually dimorphic and the neuroendocrine mechanisms governing this potential difference are not fully established. We have compared pulsatile GH secretion profiles in young men and women in the baseline state and during a continuous intravenous infusion of recombinant human insulin-like growth factor I (rhIGF-I). During the baseline study, men had large nocturnal GH pulses and relatively small pulses during the rest of the day. In contrast, women had more continuous GH secretion and more frequent GH pulses that were of more uniform size. The infusion of rhIGF-I (10 microg/kg/h) potently suppressed both spontaneous and growth hormone-releasing hormone (GHRH)-induced GH secretion in men. In women, however, rhIGF-I had less effect on pulsatile GH secretion and did not suppress the GH response to GHRH. These data demonstrate the existence of sexual dimorphism in the regulatory mechanisms involved in GH secretion in humans. The persistence of GH responses to GHRH in women suggests that negative feedback by IGF-I might be expressed, in part, through suppression of hypothalamic GHRH.

Chromosome 13q deletion mapping in pituitary tumors: infrequent loss of the retinoblastoma susceptibility gene (RB1) locus despite loss of RB1 protein product in somatotrophinomas.

Two recent studies have described allelic loss of an RB1 intragenic marker on chromosome 13q in aggressive and metastatic pituitary tumors that did not correlate with loss of pRB. The second report also showed that losses were more frequently associated with a more centromeric marker. Because both of these studies suggest the presence of another or other tumor suppressor genes (TSGs) on 13q, we carried out an allelotype analysis encompassing known and recently described TSG loci on 13q, together with immunohistochemical analysis of pRB. We analyzed 82 nonfunctional tumors and 53 somatotrophinomas subdivided into invasive and noninvasive cohorts. A significantly higher frequency of loss, at one or more of 13 markers, was evident in the invasive nonfunctional tumors (54%, 26 of 48) than in their noninvasive counterparts (29%, 10 of 34). An approximately equal frequency of loss was apparent in invasive (28%, 5 of 18) and noninvasive (31%, 11 of 35) somatotrophinomas at one or more markers. In those tumors harboring deletion, loss at two or more markers was more frequent in invasive nonfunctional tumors 65% (17 of 26) compared with 36% (4 of 11) of their noninvasive counterparts. In somatotrophinomas, 40% (2 of 5) of invasive tumors as compared with 64% (7 of 11) of noninvasive tumors had evidence of two or more deletions. In tumors showing loss at two or more loci, the majority showed large deletions; however, loss of the RB1 intragenic marker D13S153 was infrequent. In most cases, loss at individual markers was more frequent in invasive tumors than their noninvasive counterparts. A marker 3 cM telomeric to RB1 (D13S1319) showed the highest frequency of deletion in both invasive cohorts (29% of somatotrophinomas and 24% of nonfunctional tumors). Immunohistochemical analysis of pRB showed frequent loss in somatotrophinomas (27%, 9 of 33) in comparison with 4% (2 of 53) of non-functional tumors. Although loss of pRB did not correlate with loss of an intragenic marker or tumor grade, it was significantly associated with the somatotrophinoma subtype (P = 0.002). These data suggest that chromosome 13q is a frequent target for allelic deletion in pituitary tumors and point to another or other TSG loci in these regions.

Acromegaly.

In the majority of cases, acromegaly is due to GH hypersecretion by a somatotroph pituitary tumor. The etiology of acromegaly is not known, and may be related to GHRH hypersecretion, intrinsic pituitary defect, or a combination thereof. Recent physiologic data and molecular biology techniques provide insights into the pathophysiology of this condition. Treatment options include surgery, radiation, and judicious administration of pharmacologic compounds inhibiting GH secretion and tumor growth.

In vivo Investigation of Hypothalamic Secretory Activity.

The finding that all pituitary hormones are released in a discrete pulsatile fashion and that the pulsatile properties of the pituitary hormone secretion are altered in some physiologic and pathologic conditions prompted the development of techniques designed to study the pattern of release and the regulation of secretion of the hypothalamic neuropeptides. This review describes the currently used techniques to assess hypothalamic hormone secretion. (Trends Endocrinol Metab 1997;8:105-111). (c) 1997, Elsevier Science Inc.

Growth hormone therapy for hypopituitary adults: time for re-appraisal.

The advent of the production of large quantities of recombinant growth hormone (GH) has made it possible to have sufficient material to assess its efficacy in adult growth hormone deficiency (GHD). Although some studies have shown that patients who are severely deficient benefit from GH therapy, the spectrum of GHD is broad, and the degree of deficiency at times is very difficult to define. In some cases, benefit is not easily quantified, and some studies have claimed benefits that, although statistically significant, are either not clinically important or are so marginal as to be questionable in terms of cost, difficulty of administration and potential risks. The purpose here is to identify the current problems in the diagnosis of GHD, to discuss the rationale for GH therapy and to assess the potential effects of GHD as well as the benefits of GH therapy in GHD adults. We will include a commentary as to which effects appear more robust than others and which are likely to result in the greatest patient benefit. Finally, some attention will be paid to long-term safety issues that should be monitored to ensure that this medication is safe even for the patients with the greatest need.

Dexamethasone suppresses gonadotropin-releasing hormone (GnRH) secretion and has direct pituitary effects in male rats: differential regulation of GnRH receptor and gonadotropin responses to GnRH.

Endogenous or exogenous glucocorticoid excess leads to the development of hypogonadotropic hypogonadism, but the site(s) and mechanisms of glucocorticoid action are uncertain. We studied the effects of various doses of dexamethasone (Dex) on the hypothalamic-pituitary-gonadal axis in intact and castrate testosterone-replaced (cast + T) male rats and attempted to determine possible sites of Dex effects. A dose-dependent suppression of basal gonadotropin secretion was induced by 5 days of Dex treatment (20, 100, 500, or 2,500 micrograms/kg.day), and the highest dose completely abolished the postcastration rise in pituitary GnRH receptor number (GnRH-R) and serum gonadotropin levels. Administration of exogenous GnRH (0.02-200 micrograms/day over 2 days) resulted in a dose-dependent induction in GnRH-R in both intact and cast + T rats, but the effect was significantly (P less than 0.01) augmented in Dex-treated animals. In contrast, acute LH and FSH responses to GnRH (10, 25, 50, 100, or 250 ng, iv) were significantly blunted in Dex-treated rats. The data suggest that 1) Dex suppresses hypothalamic GnRH secretion, thereby preventing the postcastration rises in GnRH-R and gonadotropins; 2) at the pituitary level, Dex dissociates GnRH-R and gonadotropin responses to GnRH, augmenting GnRH-R induction by GnRH and suppressing gonadotropin responses to GnRH at a postreceptor site; and 3) the model of Dex-treated rats may be useful to study differential GnRH regulation of GnRH-R and gonadotropin secretion.

Regulation of somatic growth and the somatotropic axis by gonadal steroids: primary effect on insulin-like growth factor I gene expression and secretion.

The site-specific regulation of somatic growth by sex steroids is poorly understood. The aim of the present study was to assess the influence of 17 beta-estradiol (E2) and 5 alpha-dihydrotestosterone (DHT) on somatic growth and pituitary GH and hepatic insulin-like growth factor I (IGF-I) secretion and synthesis in the adult female rat. Animals (200-250 g) underwent sham surgery or bilateral ovariectomy. Some ovariectomized (OVX) rats were given sc implants that provided almost physiological female E2 (OVX/E2) and male DHT (OVX/DHT) levels. Animals were killed 3, 7, 14, and 26 days later. Body weight gain was calculated, and pituitary GH content, pituitary GH messenger RNA (mRNA) levels, plasma GH, and circulating IGF-I concentrations were measured. Levels of hepatic IGF-I mRNA were measured at 26 days. Ovariectomy increased body weight gain (P < 0.001) in parallel with a significant elevation in plasma IGF-I (P < 0.001). Replacement of E2 markedly suppressed somatic growth (P < 0.001), plasma IGF-I concentrations (P < 0.001), and liver IGF-I gene expression (P < 0.002). However, circulating GH concentrations were high in OVX/E2 animals (P < 0.001), whereas pituitary GH stores were significantly attenuated (P < 0.05). In contrast, DHT exposure increased body weight gain (P < 0.001), circulating IGF-I concentrations (P < 0.05), and steady state hepatic IGF-I mRNA levels (P < 0.05). Pituitary GH stores were markedly elevated (P < 0.001) in DHT-treated animals, but circulating GH levels remained very low. Pituitary GH mRNA rose transiently at 7 days in OVX and OVX/E2 rats, but no consistent changes between the groups were observed thereafter. We conclude that 1) gonadal steroids have disparate effects on somatic growth in female rats, with E2 suppressing and DHT stimulating body weight gain; 2) these effects are likely to be primarily mediated at the level of IGF-I synthesis and secretion; and 3) changes in pituitary GH content and secretion probably reflect normal adjustment to changes in the intensity of IGF-I negative feedback.

Pituitary gonadotropin-releasing hormone receptors during gonadotropin surges in ovariectomized-estradiol-treated rats.

In intact cycling rats, the number of pituitary GnRH receptors varies markedly during the estrous cycle. Concentrations are maximal on diestrus and early proestrus, before falling rapidly for a brief period immediately before the preovulatory gonadotropin surge. In this study we investigated whether dynamic changes in ovarian steroids, pituitary hormones, and GnRH itself, all of which are changing at the time of the surge, play a role in the acute transient down-regulation of the pituitary GnRH receptors. We used the ovariectomized-estradiol-treated female rat as a model, as these animals exhibit daily gonadotropin surges at a predictable time of the day and also allow studies in a situation where concentrations of ovarian steroids are stable. The pituitary GnRH binding capacity (GnRH-BC) was measured using the analog D-Ala6des Gly10-GnRH ethylamide as ligand. GnRH-BC was stable between 0900-1530 h [range, 288 +/- 29 to 262 +/- 33 fmol protein (mean +/- SE)] and fell abruptly to 123 +/- 17 fmol/mg at 1630 h, before returning to the initial level by 1730 h. This abrupt fall in GnRH-BC preceded the afternoon gonadotropin surge and was similar in timing, magnitude, and duration to that observed in intact cycling rats. Serum PRL decreased from peak levels at 1630 h, coincident with the fall in GnRH-BC, before rebounding at 1730 h. Pentobarbital given at 1400 h abolished both the gonadotropin surge and the acute fall in GnRH-BC, but did not change serum PRL levels, suggesting that PRL is not causally related to the fall in GnRH-BC. The stable morning levels of GnRH-BC were not reduced after iv injections of LH, FSH, or both hormones despite elevations in serum gonadotropins to concentrations greater than those seen during the afternoon surge. Additionally, multiple iv injections of GnRH at 30- or 10-min intervals did not decrease the stable morning levels of GnRH-BC, although serum LH and FSH were markedly elevated. The data suggest that dynamic fluctuations in ovarian steroids, gonadotropins, PRL, and GnRH are not causally related to the acute transient reduction of pituitary GnRH receptors before the afternoon gonadotropin surge. These results also suggest that another hypothalamic or pituitary factor(s) is involved in the acute regulation of GnRH receptors, and the ovariectomized-estradiol-treated rat appears to be a good model for the elucidation of the factor(s) involved.

Opioid and neurotransmitter regulation of pituitary gonadotropin-releasing hormone (GnRH) receptors in the ovariectomized estradiol-treated rat: role of altered GnRH secretion.

An acute transient fall in the number of pituitary GnRH receptors (GnRH-R) is observed before the preovulatory gonadotropin surge in cycling rats and before the afternoon daily gonadotropin surge in ovariectomized estradiol-treated rats. In the latter model, this fall can be reproduced by administration of the opioid antagonist naloxone, whereas the opioid agonist morphine acutely increases GnRH-R. In this study we investigated the mechanisms of this opioid effect and examined the effects of other neurotransmitter substances on modulation of pituitary GnRH-R. Administration of the dopaminergic agonists bromocriptine and L-dopa or the alpha-adrenergic receptor blocker phenoxybenzamine elevated GnRH-R acutely from average basal values of 240 +/- 22 and 254 +/- 21 fmol/mg protein to maximal values of 374 +/- 49, 441 +/- 67 and 461 +/- 75 fmol/mg, respectively, whereas the alpha-adrenergic agonist clonidine transiently decreased GnRH-R to 186 +/- 19 fmol/mg. Placement of radiofrequency lesions in the mediobasal hypothalamus or pretreatment with anti-GnRH serum completely abolished the ability of both morphine and naloxone to modulate the number of GnRH-R. These data indicate that the opioid-induced modulation of pituitary GnRH-R requires an intact hypothalamus and that both dopaminergic and alpha-adrenergic neurotransmitter systems may be involved. The final step of this action probably involves acute modulation of GnRH secretion (altered frequency and/or amplitude), which results in acute transient changes in the number of pituitary GnRH-R.

The "quality of life-assessment of growth hormone deficiency in adults" questionnaire: can it be used to assess quality of life in hypopituitarism?

Patients with hypopituitarism often have a multitude of physical and psychological complaints, collectively referred to as low quality of life (QoL). It has been asserted that GH deficiency (GHD) is the causative factor, and improved QoL scores have been reported during GH replacement. Qol-assessment of GHD (QoL-AGHDA) is the newest psychometric instrument with the purportedly high specificity for the issues encountered by patients with GHD. QoL-AGHDA was administered to 30 normal control subjects, 20 patients with severe GHD, and 22 patients with active acromegaly. QoL-AGHDA scores in controls (3.3 +/- 0.7) were significantly (P < 0.001) different from those in patients with hypopituitarism with unsubstituted GHD (10.6 +/- 1.5) and active acromegaly (11.6 +/- 1.6). However, QoL-AGHDA was unable to discriminate between the latter two groups, one with GHD and the other with GH excess. We conclude that as QoL-AGHDA cannot distinguish between the extremes of GH output, its ability to detect an improvement in QoL during GH replacement has to be viewed with skepticism. This can be dispelled only by double blind, placebo-controlled studies.

Evaluation of the integrity of the hypothalamic-pituitary-adrenal axis by insulin hypoglycemia test.

We retrospectively reviewed dynamic ACTH and cortisol responses to insulin hypoglycemia in 193 subjects with suspected ACTH deficiency to ascertain the predictive values of various diagnostic criteria. Based on the achievement of a peak cortisol level of 18 micrograms/dL or above, 133 subjects were classified as having an intact hypothalamic-pituitary-adrenal (HPA) axis, and 60 subjects were determined to have ACTH deficiency. Baseline and peak cortisol concentrations were strongly correlated (r = 0.63; P < 0.0001). Peak cortisol increased in parallel to ACTH increments, but plateaued at approximately 22 micrograms/dL at peak ACTH levels above approximately 75 pg/mL (r = 0.61; P < 0.0001). Basal cortisol values above 17 micrograms/dL or below 4 micrograms/dL were highly predictive of an intact or impaired HPA axis, respectively, but intermediate values had only limited sensitivity and specificity. The criteria of HPA axis integrity, defined as an increment in plasma cortisol of more than 7 micrograms/dL above the baseline or as a doubling of the baseline cortisol value, were associated with high false positive and false negative rates. We conclude that 1) the baseline morning serum cortisol concentration has very limited predictive power in differentiating between normal and impaired HPA function; 2) the use of criteria based on incremental changes in serum cortisol from baseline leads to unacceptably high false positive and false negative rates; and 3) insulin hypoglycemia is still the best indicator of the integrity of the response of the HPA axis to stress.

Regulation of pulsatile growth hormone secretion by fasting in normal subjects and patients with acromegaly.

In acromegaly, GH hypersecretion occurs despite elevated insulin-like growth factor-I (IGF-I) levels, implying defective IGF-I feedback. To study the possible mechanisms of defective IGF-I negative feedback in acromegaly, we assessed parameters of pulsatile GH secretion during fasting-induced decrease in plasma IGF-I. Seven patients with active acromegaly and six normal controls were fasted for 6 days and GH secretory profiles were obtained by frequent (every 10 min) blood sampling for 24 h and analyzed by Cluster. Fasting resulted in similar decreases in IGF-I, body weight, and blood glucose levels, and increases in free fatty acid and beta-hydroxybutyrate in all subjects. Normal subjects showed increases in 24-h total and pulsatile GH production, GH pulse frequency, maximal pulse amplitude, interpulse and nadir levels, implying suppression of hypothalamic somatostatin secretion and increase in GH-releasing hormone (GHRH) pulse frequency. In acromegalic patients, GH (and, by inference, GHRH) pulse frequency was unchanged. Three patients had increases in GH production, interpulse, and nadir levels similar to the normals while the other four had no change or paradoxical decreases in these parameters. Percentage change in GH production was highly correlated with percentage change in interpulse and nadir levels in both normals and patients. Mean GH response to GHRH (0.33 micrograms/kg iv) did not change significantly in any group as a result of fasting. Our data suggest that in healthy humans IGF-I negative feedback on GH secretion involves suppression of GHRH pulse frequency. GH (and, by inference, GHRH) pulse frequency is resistant to decrease in IGF-I in acromegaly, suggesting that lowered sensitivity of GHRH neurons to IGF-I may be the mechanism of high GH pulse frequency in this disease.

Plasma insulin-like growth factor-I/somatomedin-C in acromegaly: correlation with the degree of growth hormone hypersecretion.

We measured plasma insulin-like growth factor I/somatomedin-C (IGF-I/SmC) concentrations and mean 24-h GH secretion serially before and during therapy with the long-acting somatostatin analog SMS 201-995 in 21 patients with acromegaly. When mean plasma GH was elevated above 12.0 +/- 0.6 (+/- SE) micrograms/L, plasma IGF-I/SmC concentrations were uniformly high, but a decline of mean plasma GH below this value was accompanied by a linear decrease in IGF-I/SmC concentrations (r = 0.89; P less than 0.001). Even mildly abnormal mean GH concentrations (greater than 4.6 but less than 10 micrograms/L) were accompanied by high plasma IGF-I/SmC values. The log dose-response interrelation between mean 24-h plasma GH and IGF-I/SmC concentrations was linear (r = 0.86; P less than 0.001). We conclude that 1) an excellent log dose-response correlation between mean 24-h plasma GH and IGF-I/SmC concentrations is present in patients with acromegaly; 2) normalization of plasma IGF-I/SmC occurs only in patients with mean daily GH output within the normal range; and 3) determination of plasma IGF-I/SmC is an accurate indicator of normalcy of GH secretion and should be used in the diagnosis of active acromegaly as well as in monitoring the progress of therapy.

Analysis of mammosomatotropic cells in normal and neoplastic human pituitary tissues by the reverse hemolytic plaque assay and immunocytochemistry.

The reverse hemolytic plaque assay (RHPA) was used to study hormone release from cultured normal and neoplastic human pituitary cells. The RHPA revealed a lower percentage of GH- and PRL-producing cells in normal and neoplastic pituitaries compared to the percentage of these cells revealed by immunocytochemical (ICC) staining for GH and PRL. Normal pituitary tissues as well as some PRL- or GH-producing adenomas contained large numbers of mammosomatotropic (MS) cells when analyzed by RHPA, combined RHPA-ICC, and ultrastructural immunohistochemistry with immunogold labeling. The percentage of GH and PRL cells in normal pituitaries ranged from 37-51% and 30-60%, respectively, by RHPA, while the percentage of MS cells ranged from 29-49%. The percentage of GH and PRL cells in normal pituitaries estimated by ICC ranged from 53-65% and 32-55%, respectively, while the percentage of MS cells estimated with this technique ranged from 26-50%. Double labeling with the immunogold technique detected GH and PRL in the same cells and within the same granules in both normal and neoplastic pituitary cells. These results indicate that MS cells are present in normal human pituitaries as well as in some pituitary adenomas, and in some pituitaries these two hormones are stored within the same secretory granules.

Ectopic prolactinoma in a patient with hyperparathyroidism and abnormal sellar radiography.

In a patient with hyperparathyroidism and chronic renal failure due to polycystic kidney disease, a finding of destroyed sellar and parasellar structures and hyperprolactinemia suggested the diagnosis of invasive pituitary prolactinoma. At surgery no tumor was found, and pathological examination of the sphenoid bone revealed a parathyroid bone lesion (brown tumor) as well as ectopic prolactinoma in the clivus. This patient demonstrates that a tumor may develop in ectopic pituitary tissue. The combination of radiographically abnormal sellar structures with pituitary hormone hypersecretion should not be regarded as absolute proof of a pituitary adenoma.

The growth hormone (GH) response to GH-releasing peptide (His-DTrp-Ala-Trp-DPhe-Lys-NH2), GH-releasing hormone, and thyrotropin-releasing hormone in acromegaly.

In patients with acromegaly, GH-producing pituitary tumors release GH in response to specific stimuli such as GH-releasing hormone (GHRH) and are also responsive to a variety of nonspecific stimuli, such as TRH or GnRH, and may exhibit paradoxical responses to glucose and dopamine. In healthy humans, the synthetic peptide GH-releasing peptide (GHRP) (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) releases GH by a putative mechanism of action that is independent of GHRH. How these tumors respond to GHRP is not well characterized. We studied the GH responses to GHRH, GHRP, and TRH stimulation in 11 patients with active acromegaly. The peak GH responses to GHRP and GHRH were not correlated (r = 0.57; P = 0.066). In contrast, the peak GH responses to GHRP and TRH were highly correlated (r = 0.95; P < 0.001). In conclusion, in patients with acromegaly, the GH response to GHRP is qualitatively normal and does not appear to depend on GHRH.